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Bilirubin metabolism
Authors: Namita Roy-Chowdhury, PhD, FAASLD, Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD
Section Editors: Sanjiv Chopra, MD, MACP, Elizabeth B Rand, MD
Deputy Editor: Shilpa Grover, MD, MPH, AGAF

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2022. | This topic last updated: Oct 05, 2020.

INTRODUCTION

Bilirubin is the catabolic product of heme metabolism. Within physiologic range, bilirubin
has cytoprotective and beneficial metabolic effects, but in high levels it is potentially toxic.
Fortunately, there are elaborate physiologic mechanisms for its detoxification and
disposition. Understanding these mechanisms is necessary for interpretation of the clinical
significance of high serum bilirubin concentrations. Furthermore, because bilirubin shares
its metabolic pathway with various other sparingly water soluble substances that are
excreted in bile, understanding bilirubin metabolism also provides insight into the
mechanisms of transport, detoxification, and elimination of many other organic anions [1].

An overview of the major aspects of bilirubin formation and disposition will be reviewed
here. The settings in which bilirubin disposition is impaired will also be discussed briefly.
Clinical aspects of serum bilirubin determination, the evaluation of patients with
hyperbilirubinemia, and the classification of causes of jaundice are presented separately.
(See "Clinical aspects of serum bilirubin determination" and "Diagnostic approach to the
adult with jaundice or asymptomatic hyperbilirubinemia" and "Classification and causes of
jaundice or asymptomatic hyperbilirubinemia".)

FORMATION OF BILIRUBIN

Bilirubin is formed by breakdown of heme present in hemoglobin, myoglobin, cytochromes,

catalase, peroxidase and tryptophan pyrrolase. Eighty percent of the daily bilirubin
production (250 to 400 mg in adults) is derived from hemoglobin [2]; the remaining 20
percent being contributed by other hemoproteins and a rapidly turning-over small pool of
free heme. Enhanced bilirubin formation is found in all conditions associated with

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increased red cell turnover such as intramedullary or intravascular hemolysis (eg,

hemolytic, dyserythropoietic, and megaloblastic anemias).

Heme consists of a ring of four pyrroles joined by carbon bridges and a central iron atom
(ferroprotoporphyrin IX). Bilirubin is generated by sequential catalytic degradation of heme
mediated by two groups of enzymes:

● Heme oxygenase
● Biliverdin reductase

Heme oxygenase initiates the opening of the porphyrin ring of heme by catalyzing the
oxidation of the alpha-carbon bridge ( figure 1). This leads to formation of the green
pigment, biliverdin, which is then reduced by the biliverdin reductase to the orange-yellow
pigment bilirubin IX-alpha. Iron is released in this process, and the oxidized alpha-bridge
carbon is eliminated as carbon monoxide (CO). Measurement of intrinsic CO production has
been used to quantify bilirubin production [3].

Heme oxygenase is present in the high concentrations in reticuloendothelial cells of the

spleen, the principal site of red cell breakdown, and in the Kupffer cells in the liver [4]. It is
also induced by heme (eg, in hemolytic states).

Heme oxygenase is rate-limiting in bilirubin production [5]. As an example, pharmacologic

inhibition of heme oxygenase by tin-protoporphyrin or tin-mesoporphyrin reduces bilirubin
production [6].

Carriage in plasma and conversion to water-soluble products — Bilirubin is very poorly

soluble in water at physiologic pH because of internal hydrogen bonding that engages all
polar groups and gives the molecule a contorted "ridge-tile" structure [7]. The fully
hydrogen-bonded structure of bilirubin is designated bilirubin IX-alpha-ZZ. Water-insoluble
unconjugated bilirubin is associated with all known toxic effects of bilirubin. Thus, the
internal hydrogen bonding prevents bilirubin elimination and is critical in producing
bilirubin toxicity. In the plasma, albumin-binding keeps it water soluble. Subsequent
conversion of bilirubin IX-alpha to a water-soluble form, by disruption of the hydrogen
bonds, is essential for its elimination by the liver and kidneys. This is achieved by glucuronic
acid conjugation of the propionic acid side chains of bilirubin. Bilirubin glucuronides are
water-soluble and are readily excreted in bile. Bilirubin is primarily excreted in normal
human bile as the diglucuronide; unconjugated bilirubin accounts for only 1 to 4 percent of
pigments in normal bile.

During phototherapy, which is used to reduce serum bilirubin concentrations in babies with
severe neonatal hyperbilirubinemia, configurational and structural photoisomers of
bilirubin are produced [8]. These isomers lack hydrogen bonding and are excreted into bile

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without further metabolism. In the bile, the configurational isomers may partly revert to the
hydrogen-bonded bilirubin-IXalpha-ZZ.

Measurement of serum bilirubin — Reaction of bilirubin with diazo reagents causes

breakdown of the tetrapyrrole to two azodipyrroles (the van den Bergh reaction) [9] which
can be readily measured spectrophotometrically. Diazo assays are most commonly used for
quantification of bile pigments for clinical purposes via the following sequence.

● Because the central carbon bridge of bilirubin is buried within the molecule by
hydrogen bonds, unconjugated bilirubin reacts slowly with the diazo reagent. In
comparison, conjugated bilirubin, which lacks hydrogen bonds, reacts rapidly even in
the absence of accelerators ("direct" van den Bergh reaction).

● On disruption of hydrogen bonds by addition of "accelerators" such as methanol or

caffeine, the reaction is completed rapidly (total bilirubin).

● Unconjugated bilirubin ("indirect" bilirubin) concentration is calculated by subtracting

the direct-reacting fraction from total bilirubin.

Direct reacting bilirubin slightly overestimates the conjugated bilirubin concentration

because a fraction of unconjugated bilirubin (about 10 to 15 percent) also gives a direct van
den Bergh reaction. There are several other potential sources of error. As an example,
endogenous substances, such as plasma lipids, and drugs, such as propranolol, interfere
with the diazo assay. This can produce unreliable results, but only when the bilirubin
concentration is normal or slightly elevated. Albumin-bilirubin complexes (delta-bilirubin)
also may give a direct reaction. More accurate and sensitive quantification of bilirubin
requires chromatographic analysis such as high performance liquid chromatography and
reflectance fluorimetry [10-12].

METABOLISM OF BILIRUBIN

A number of steps are involved in the metabolism of bilirubin ( figure 2).

Albumin binding of bilirubin in plasma — Binding to albumin and, to a much lesser

degree, high density lipoprotein, keeps bilirubin in solution in plasma; only a small fraction
of bilirubin circulates in the unbound state. Binding to high density lipoprotein may become
significant in states of severe hypoalbuminemia.

Albumin binding keeps bilirubin in the vascular space, thereby preventing its deposition
into extrahepatic tissues, including sensitive tissues such as the brain, and minimizing
glomerular filtration. It also transports bilirubin to the sinusoidal surface of the hepatocyte,

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where the pigment dissociates from albumin and enters the hepatocyte (see 'Uptake and
storage of bilirubin by hepatocytes' below).

Free bilirubin can cause cerebral toxicity when the molar concentration of bilirubin exceeds
that of albumin (see 'Bilirubin toxicity' below). On the other hand, the plasma bilirubin
content increases after albumin infusion because of transfer of the pigment from tissue
stores to the intravascular space.

Several other ligands bind to albumin at the same site as bilirubin, including sulfonamides,
warfarin, antiinflammatory drugs, and cholecystographic contrast media. These agents can
displace bilirubin from albumin, thereby precipitating bilirubin encephalopathy in newborns
without an alteration in the total serum bilirubin concentration [13]. Many other
compounds such as fatty acids bind at a different albumin site but may, in some cases,
reduce the binding constant of albumin for bilirubin [14].

Albumin binding of bilirubin is usually reversible. However, irreversible binding can occur in
the presence of prolonged conjugated hyperbilirubinemia (eg, during biliary obstruction).
The bilirubin fraction irreversibly bound to albumin (delta-bilirubin) is not cleared by the
liver or the kidney and, because of the long half-life of albumin, lingers in the plasma [15].
This may result in prolonged hyperbilirubinemia after endoscopic or surgical relief of biliary
obstruction. Because delta-bilirubin gives a "direct" diazo reaction, this may give a false
impression of a persistent blockage of the bile ducts [16]. The presence of delta-bilirubin
can be inferred by the absence of bilirubin excretion in the urine despite the apparent
presence of direct hyperbilirubinemia and can be identified by high performance liquid
chromatography of serum ( figure 3).

Uptake and storage of bilirubin by hepatocytes — In the liver sinusoids, the albumin-
bilirubin complex dissociates, and the bilirubin is taken up efficiently by the hepatocyte
while the albumin remains in the circulation. Bilirubin is taken up by hepatocytes by a
process of facilitated diffusion, which is not energy-consuming; as a result, transport
cannot occur against a concentration gradient, and is bidirectional. Defects in the specific
transporters that mediate each of the steps in bilirubin transport can lead to
hyperbilirubinemia. (See "Inherited disorders associated with conjugated
hyperbilirubinemia" and "Gilbert syndrome and unconjugated hyperbilirubinemia due to
bilirubin overproduction".)

Sinusoidal bilirubin uptake requires inorganic anions, such as chloride, and is thought to be
mediated by carrier proteins which have not been fully characterized [17,18]. Passage of
bilirubin across the hepatocyte sinusoidal surface membrane is bidirectional. Normally,
canalicular excretion, rather than sinusoidal uptake or glucuronidation in the endoplasmic
reticulum, is rate limiting for bilirubin throughput. Bilirubin entering the hepatic sinusoids is
efficiently extracted by hepatocytes close to its point of entry (ie, periportal region). A
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fraction of the unconjugated and conjugated bilirubin within the hepatocytes is

transported back into the sinusoidal blood. This fraction undergoes re-uptake by
hepatocytes downstream to the sinusoidal blood flow. The re-uptake is mediated by two
proteins, organic anion transporter protein 1B1 and 1B3 (OATP1B1 and OATP1B3), encoded
by the genes SLCO1B1 and SLCO1B3. This results in the recruitment of additional
hepatocytes in this process, thereby increasing the net bilirubin excretory capacity of the
liver [19]. Within the hepatocyte, bilirubin and other organic anions bind to glutathione S-
transferases (GSTs). GST-binding reduces the efflux of the internalized bilirubin, thereby
increasing net uptake ( figure 2).

This process of bilirubin uptake is impaired in certain disease states:

● Bilirubin uptake is inhibited by certain drugs (eg, rifampin, flavaspidic acid, and
cholecystographic dyes).

● The re-uptake of conjugated and unconjugated bilirubin is disrupted in Rotor

syndrome, which is caused by mutations or deletion of both SLCO1B1 and SLCO1B3,
resulting in loss of function of both OATP1B1 and OATP1B3. (See "Inherited disorders
associated with conjugated hyperbilirubinemia".)

● In patients with cirrhosis, a portion of the bilirubin produced in the spleen may bypass
the liver via portosystemic collaterals. Furthermore, the sinusoidal endothelium, which
is normally fenestrated, may lose the fenestrae (capillarization), thereby creating a
barrier between the plasma and the hepatocytes. As a result, serum unconjugated
bilirubin concentrations often increase in this condition.

Conjugation of bilirubin — Glucuronidation of bilirubin, a large variety of endogenous

compounds (eg, steroid hormones, thyroid hormones, catecholamines), and a wide array of
exogenous substrates (eg, drugs, toxins, carcinogens and laboratory xenobiotics) is
mediated by a family of enzymes, termed uridine-diphosphoglucuronate
glucuronosyltransferase (UGT) ( figure 2) [20]. As noted above, glucuronides are more
water soluble, and are readily excreted in bile and urine.

Enzyme-catalyzed glucuronidation is one of the most important detoxification mechanisms

of the body. Of the various isoforms of the UGT family of enzymes, only one isoform,
UGT1A1 is physiologically important in bilirubin glucuronidation ( figure 3) [21]. UGT1A1 is
an intrinsic protein of the endoplasmic reticulum (ER) and its catalytic site is located within
the ER lumen. Therefore, the sugar donor substrate uridine diphosphate glucuronic acid
(UDPGA) must enter the ER luminal space for conjugation. UDP-N-acetylglucosamine is the
natural stimulator of the transport of the polar substrate, UDPGA into the ER lumen. It has
been suggested that four nucleotide sugar transporter proteins mediate UDP-N-
acetylglucosamine stimulation of UDGPA transport [22].

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Bilirubin diglucuronide is the predominant pigment in normal adult human bile,

representing over 80 percent of the pigment. However, in subjects with reduced bilirubin-
UGT activity, the proportion of bilirubin diglucuronide decreases, and bilirubin
monoglucuronide may constitute more than 30 percent of the conjugates excreted in bile.
Reduction of conjugating enzyme activity to approximately 30 percent of normal results in a
mild but discernible increase in serum bilirubin concentrations. (See "Gilbert syndrome and
unconjugated hyperbilirubinemia due to bilirubin overproduction".)

Inhibitory factor(s) for hepatic UGT1A1 is secreted in the milk of some mothers (breast milk
jaundice). In other cases, an inhibitory factor present in maternal plasma may be
transplacentally transferred to the fetus (the Lucey Driscoll syndrome). UGT1A1 deficiency
also may be seen in neonates, chronic hepatitis, and in certain inherited disorders (Gilbert
syndrome and Crigler-Najjar syndrome I and II).

Excretion of conjugated bilirubin — Conjugated bilirubin and other substances destined

to be excreted in bile are secreted across the bile canalicular membrane of the hepatocyte
against a concentration gradient that may reach 1:1000, indicating the presence of active
transport [23]. Among the four types of canalicular transporters, the multispecific organic
anion transporter, also termed multidrug resistance protein 2 or ATP-binding cassette (ABC)
C2 (cMOAT/MRP2/ABCC2), appears to be the most important for the canalicular secretion of
bilirubin and many other organic anions, with the exception of bile acids ( figure 2) [24].
Interestingly, a portion of the conjugated bilirubin is secreted back into the sinusoidal blood
via the ATP hydrolysis-coupled pump ABCC3. Reuptake of the conjugated bilirubin by
hepatocytes downstream to the sinusoidal blood flow is mediated by the sinusoidal surface
organic anion transporters OATP1B1 and OATP1B3. The recruitment of additional
hepatocytes increases the hepatic excretory capacity for conjugated bilirubin, which is rate
limiting in bilirubin throughput [19].

Enhanced bile flow (eg, by infusion of bile salts) or phenobarbital treatment increases the
maximal bilirubin excretory capacity. On the other hand, the excretion of conjugated
bilirubin is impaired in a number of acquired conditions (eg, alcoholic or viral hepatitis,
cholestasis of pregnancy) and inherited disorders (eg, Dubin-Johnson syndrome, Rotor
syndrome, benign recurrent intrahepatic cholestasis). It can also be caused by a variety of
drugs (eg, alkylated steroids, chlorpromazine). (See "Classification and causes of jaundice
or asymptomatic hyperbilirubinemia" and "Gilbert syndrome and unconjugated
hyperbilirubinemia due to bilirubin overproduction" and "Inherited disorders associated
with conjugated hyperbilirubinemia".)

Degradation of bilirubin in the digestive tract — Bile pigment appearing in bile is mostly

(more than 98 percent) conjugated. Conjugated bilirubin is water soluble and is not
absorbed across the lipid membrane of the small intestinal epithelium; in comparison, the

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unconjugated bilirubin fraction is partially reabsorbed and undergoes enterohepatic

circulation ( figure 4) [25]. This fraction increases during phototherapy because of the
excretion of photoisomers of bilirubin. Oral administration of charcoal, agar, or
cholestyramine may interfere with the absorption of unconjugated bilirubin, thereby
increasing the efficacy of phototherapy. In contrast, excessive amounts of bilirubin are
available for reabsorption in neonates with obstruction of the upper intestinal tract,
delayed passage of meconium, or fasting; this may increase the intensity and duration of
neonatal jaundice.

Bilirubin is reduced by bacterial enzymes in the colon to a series of molecules, termed

urobilinogens [26]. The two major urobilinoids found in stool, urobilinogen and
stercobilinogen, are colorless and turn orange-yellow only after oxidation to urobilins. In
complete biliary obstruction or severe intrahepatic cholestasis (eg, in the early phase of
acute viral hepatitis), feces may take the appearance of china clay. Thus, the absence of
urobilinogen in stool and urine in a jaundiced patient indicates complete biliary obstruction.
Urobilinogens and their derivatives are partly absorbed from the bowel, undergo
enterohepatic recycling, and are eventually excreted in urine and feces (see 'Urobilinogen'
below) ( figure 4).

The intestinal microflora influence serum levels of bilirubin. In a study in Gunn rats (which
have a congenital deficiency of bilirubin UDP-glucuronosyltransferase), treatment with oral
clindamycin and neomycin resulted in the disappearance of fecal urobilinoids while serum
bilirubin increased dramatically (from 10.8 mg/dL [186 micromol/L] to 17 mg/dL [289
micromol/L]) [27]. Intestinal colonization with Clostridium perfringens led to reappearance of
fecal urobilinoid production accompanied by a partial decrease in serum bilirubin levels.
The authors speculated that prolonged use of certain antibiotics may lead to an increase in
serum bilirubin levels in humans. Patients with abnormal bilirubin conjugation may be at
particular risk.

Alternative pathways of bilirubin elimination — Alternative pathways of bilirubin

elimination may be important in certain clinical settings. One such pathway is oxidation of
bilirubin by mixed function oxidases in liver and other organs. In addition, induction of
cytochrome P-450c by chlorpromazine reduced the serum bilirubin concentration in one
patient with Crigler-Najjar syndrome type I (enzyme catalyzed oxidation) [28].

In conditions associated with elevated conjugated plasma bilirubin concentrations (eg,

intrahepatic or extrahepatic cholestasis), the kidney is responsible for 50 to 90 percent of
conjugated bilirubin excretion [29,30]. However, bile remains the main excretion route for
unconjugated hyperbilirubinemia.

Urobilinogen — Urobilinogen is produced by bacterial breakdown of bilirubin excreted in

bile into the bowel. It is partly absorbed in the bowel and undergoes hepatobiliary
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recirculation. The fraction that is not cleared by the liver enters the general circulation and
is partly excreted in urine. As a result, urinary urobilinogen excretion may be increased in
the following situations:

● Excessive bilirubin production (eg, in cases of hemolysis or absorption of hematoma)

● Inefficient hepatic clearance of the reabsorbed urobilinogen (eg, in patients with
cirrhosis or at some stages of hepatitis)
● Excessive exposure of bilirubin to intestinal bacteria (eg, constipation or bacterial
overgrowth).

By contrast, urinary urobilinogen excretion can be reduced or abolished in near-complete

biliary obstruction (eg, carcinoma of the pancreas) or severe cholestasis (eg, in early stages
of viral hepatitis).

Standard clinical tests for urobilinogen do not distinguish between normal and low urinary
urobilinogen levels. Furthermore, urobilinogen excretion can be reduced, normal, or
elevated in patients with hepatitis as noted above. Tubular reabsorption and instability of
the pigment in acid urine can also influence results. Because of these complexities, tests for
urinary urobilinogen are usually not useful in the differential diagnosis of liver diseases.

BILIRUBIN IN DISEASE STATES

In normal plasma, about 4 percent of bilirubin is conjugated. This relationship may vary in
disease states:

● In inherited disorders of bilirubin conjugation, the proportion of conjugated bilirubin

is reduced.

● In Rotor syndrome (defect in re-uptake of conjugated and unconjugated bilirubin) and

in Dubin-Johnson syndrome (defect in canalicular excretion of bilirubin), both
conjugated and unconjugated bilirubin accumulate in plasma [19].

● In biliary obstruction or hepatocellular diseases, both conjugated and unconjugated

bilirubin accumulate in plasma [15].

● In hemolytic jaundice, total plasma bilirubin increases, but the proportion of the
unconjugated and conjugated fractions remains unchanged.

Bilirubin binds to the elastic tissue of skin and sclera, and is also found in all tissue fluids
with a high albumin content. The usual tight but reversible binding to albumin precludes
glomerular filtration of unconjugated bilirubin; similar principles apply to irreversible
covalently bound bilirubin (delta-bilirubin). In contrast, conjugated bilirubin is less strongly

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bound to albumin and can be excreted in the urine. Thus, the finding of bilirubin in the
urine, in the absence of albuminuria, indicates the presence of an increased amount of
conjugated bilirubin in the plasma.

Potential beneficial effects of bilirubin — Although clinicians are generally concerned

with serum bilirubin levels as a marker of liver disease and the direct toxicity of bilirubin
(see 'Bilirubin toxicity' below), within a near-physiological range of serum bilirubin
concentrations, the antioxidative action of bilirubin may provide beneficial effects. An
inverse relationship between serum bilirubin levels and risk of ischemic coronary artery
disease has been reported in middle-aged British men [31]. A population study in Belgium
showed an inverse relationship between serum bilirubin levels and cancer mortality [32].
More recently, the study of a very large number of subjects in the United States revealed
that the odds ratio for the history of colorectal cancer is reduced to 0.295 in men and 0.186
in women per 1 mg/dL increment in serum bilirubin levels [33]. Subjects with mild elevation
of plasma bilirubin were reported to have lower levels of abdominal obesity and reduced
risk of metabolic syndrome, suggesting a protective role of bilirubin against obesity and
insulin resistance [34]. Conversely, obese subjects with visceral obesity and elevated insulin
levels were found to have lower plasma bilirubin [35]. However, such statistical associations
do not conclusively prove a causative role of bilirubin. In addition to biliverdin (and
bilirubin), the other products of hemeoxygenase-mediated heme breakdown (namely iron
and CO) may also have physiological roles in the liver. As an example, one study found that
induction or overexpression of heme oxygenase attenuated the replication of hepatitis C
virus [36].

Bilirubin toxicity — Unconjugated bilirubin is toxic to many cells and organelles.

Physiologic mechanisms that protect against bilirubin toxicity include, as described above,
binding to plasma albumin, and rapid uptake, conjugation, and clearance by the liver.
Because of these efficient protective mechanisms, the harmful effects of unconjugated
bilirubin is limited to neonates with a high degree of unconjugated hyperbilirubinemia and
subjects with inherited disorders of bilirubin conjugation.

Markedly elevated serum unconjugated bilirubin concentrations (usually over 20 mg/dL) in

the newborn may result in clinical evidence of brain damage, ranging from subtle
neurologic abnormalities to severe encephalopathy or permanent bilirubin-induced
neurologic damage (BIND; commonly known as kernicterus) to death [37]. The serum
concentration at which clinical signs of neurotoxicity occur is variable and is influenced by
many factors such as protein-binding of bilirubin, putative bilirubin transporters in the
brain, and enzymes in the central nervous system that oxidize bilirubin [38]. (See
"Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and
clinical manifestations", section on 'Chronic bilirubin encephalopathy (kernicterus)'.)

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SUMMARY AND RECOMMENDATIONS

● Bilirubin is formed by the breakdown of heme present in hemoglobin, myoglobin,

cytochromes, catalase, peroxidase, and tryptophan pyrrolase. Eighty percent of the
daily bilirubin production (250 to 400 mg in adults) is derived from hemoglobin. (See
'Formation of bilirubin' above.)

● Bilirubin is very poorly soluble in water at physiologic pH because of internal hydrogen

bonding that engages all polar groups and gives the molecule a contorted "ridge-tile"
structure. The conversion of bilirubin IX-alpha to a water-soluble form by disruption of
the hydrogen bonds is essential for the elimination by the liver and kidney. (See
'Carriage in plasma and conversion to water-soluble products' above.)

● A number of steps are involved in the metabolism of bilirubin ( figure 2). (See
'Metabolism of bilirubin' above.)

● In normal plasma, about 4 percent of bilirubin is conjugated. This relationship may

vary in disease states. (See 'Bilirubin in disease states' above.)

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GRAPHICS

Bilirubin synthesis

Conversion of heme to biliverdin and then bilirubin. Heme ring-

opening at the alpha-carbon bridge of heme is catalyzed by heme
oxygenase, resulting in the formation of biliverdin. This is followed
by reduction of biliverdin to bilirubin in a reaction catalyzed by
biliverdin reductase.

NADH: reduced nicotinamide adenine dinucleotide; NADPH:

reduced nicotinamide adenine dinucleotide phosphate.

Graphic 65197 Version 2.0

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Bilirubin throughput in hepatocytes

Schematic representation of the steps involved in bilirubin (B)

throughput in hepatocytes: transport to the liver (primarily as
albumin-bound bilirubin), uptake at the sinusoidal membrane,
intracellular binding, conjugation (glucuronidation), and canalicular
excretion. Sinusoidal bilirubin uptake requires inorganic anions
such as chloride, and is thought to be mediated by carrier proteins.
Within the hepatocyte, bilirubin binds to glutathione S-transferases
(GSTs). GST-binding reduces the efflux of the internalized bilirubin,
thereby increasing the net uptake. GSTs also bind bilirubin
glucuronides (BG) prior to excretion. Bilirubin also enters
hepatocytes by passive diffusion. Glucuronidation of bilirubin is
mediated by a family of enzymes, termed uridine
diphosphoglucuronosyltransferase (UGT), the most important of
which is bilirubin-UGT-1 (UGT1A1). Conjugated bilirubin is secreted
actively across the bile canalicular membrane of the hepatocyte
against a concentration gradient that may reach 1:1000. The
canalicular multi-drug resistance protein 2 (MRP2) appears to be
the most important for the canalicular secretion of bilirubin. A
portion of the conjugated bilirubin is transported into the
sinusoidal blood via the ATP hydrolysis-couple pump, ABCC3, to
undergo reuptake via OATP1B1 and OATP1B3 by hepatocytes
downstream to the sinusoidal blood flow.

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UDP: uridine diphosphate; UDPGA: uridine 5'-diphosphoglucuronic

acid; ABCC3: ATP-binding cassette subfamily C number 3; OATP1B1:
organic anion-transporting polypeptide 1B1; OATP1B3: organic
anion-transporting polypeptide 1B3.

Graphic 52393 Version 4.0

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UDP-glucuronosyltransferases (UGT)

Graphic 65615 Version 1.0

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Enterohepatic and systemic circulation of bilirubin

and its metabolites in adults

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Contributor Disclosures
Namita Roy-Chowdhury, PhD, FAASLD No relevant financial relationship(s) with ineligible companies
to disclose. Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD No relevant financial relationship(s)
with ineligible companies to disclose. Sanjiv Chopra, MD, MACP No relevant financial relationship(s)
with ineligible companies to disclose. Elizabeth B Rand, MD No relevant financial relationship(s) with
ineligible companies to disclose. Shilpa Grover, MD, MPH, AGAF No relevant financial relationship(s)
with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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